A promising and widely studied example of vertebrate synaptic plasticity is long-term potentiation (LTP), the persistent synaptic enhancement seen following a brief period of coincident pre- and postsynaptic activity. The cellular and molecular mechanisms responsible for LTP will likely elucidate physiological and pathological phenomena including learning, memory, developmental synapse specificity, neuronal death, and dementia. The cellular signaling responsible for generating LTP has been studied extensively. There is now compelling evidence that there is delivery of AMPA-type glutamate receptors to synapses during LTP. Here we will examine the cellular and molecular mechanisms of AMPA receptor delivery to synapses. We will characterize constitutive and regulated synaptic delivery. A specific model is proposed and tested. A regulated pathway effects transient delivery of receptors. The increased levels of receptors at synapses are maintained by constitutive one-for-one exchange between intracellular and synaptic pools. These issues will be examined with several complementing methodologies including electrophysiology, two-photon imaging of GFP-tagged receptors, molecular biology and transgenic technology. These studies will use rodent hippocampal slices (acute and organotypic). In this grant period we plan to: 1. measure delivery of recombinant AMPA receptors to synapses 2. determine which AMPA receptor subunits and domains control constitutive and regulated synaptic delivery 3. generate transgenic mice with dominant negative AMPA-receptor mutations that perturb regulated or constitutive delivery